(cid:9) (cid:9)
`
`(54) SUBSTITUTED NAPHTHALENES
`
`(75) Inventors: (cid:9)
`
`Thomas G. Gant, Carlsbad, CA
`(US); Sepehr Sarshar, Cardiff by
`the Sea, CA (US)
`
`Correspondence Address:
`GLOBAL PATENT GROUP - APX
`Ms. LaVern Hall
`10411 Clayton Road, Suite 304
`ST. LOUIS, MO 63131 (US)
`
`(73) Assignee: (cid:9)
`
`(21) Appl. No.: (cid:9)
`
`(22)
`
`Filed:
`
`AUSPEX
`PHARMACEUTICALS, INC.,
`Vista, CA (US)
`
`12/116,636
`
`May 7, 2008
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/928,343, filed on May
`8, 2007.
`
`Publication Classification
`
`(51) Int. Cl.
`A61K 31/165 (cid:9)
`C07C 233/05 (cid:9)
`
`(2006.01)
`(2006.01)
`
`III III a IIOI OlD IIO III IO 1101 OII IO 1101 101 II olio II OI IIi
`
`U. w, ^,o,n.i
`
`(19) United States
`(12) Patent Application Publication
`Gant ..i al. (cid:9)
`
`(43) Pub. Date: (cid:9)
`
`2008/02 80991
`I l.9E0u%
`Nov.
`
`(52) (cid:9) U.S. Cl .......................................... 514/630; 564/219
`
`(57) (cid:9)
`
`ABSTRACT
`
`Disclosed herein are substituted naphthalene-based melato-
`nin (MT) receptor modulators and/or 5-HT receptor modula-
`tors of Formula I, process of preparation thereof, pharmaceu-
`tical compositions thereof, and methods of use thereof.
`
`Formula I
`
`0
`
`R14 ^ (cid:9)
`N
`
`Rl5
`
`Rl6
`
`R17
`
`R13
`Z12
`
`Z7
`
`Apotex Ex. 1009
`
`Apotex v. Auspex
`IPR2021-01507
`
`(cid:9)
`(cid:9)
`

`

`US 2008/0280991 Al
`
`Nov. 13, 2008
`
`SUBSTITUTED NAPHTHALENES
`
`[0001] This application claims the benefit of priority of
`U.S. provisional application No. 60/928,343, filed May 8,
`2007, the disclosure of which is hereby incorporated by ref-
`erence as if written herein in its entirety.
`
`FIELD
`
`[0002] The present invention is directed to naphthalene-
`based 5-HT receptor modulators and/or melatonin receptor
`modulators, pharmaceutically acceptable salts and prodrugs
`thereof, the chemical synthesis thereof, and medical use of
`such compounds for the treatment and/or management of
`5-HT receptor-mediated disorders and/or melatonin receptor-
`mediated disorders.
`
`BACKGROUND
`
`[0003] Agomelatine (Valdoxan®, S 20098), N-[2-(7-meth-
`oxy-naphthalen-1-yl)-ethyl]-acetamide, is an orally adminis-
`tered putative agonist of the melatonin MT, and MT 2 recep-
`tors. Agomelatine also antagonizes the 5-HT 2C receptor.
`Another drug of agomelatine's class is Ramelteon (Roza-
`rem®). Ramelton, however, does not elicit the same effect on
`5-HT2C receptors as agomelatine, and therefore is not as
`effective as agomelatine in treating certain disorders. Ago-
`melatine can be used to treat sleep disorders and depressive
`disorders. As compared with other sleep disorder and depres-
`sive disorder medications, agomelatine does not cause sexual
`side-effects, daytime drowsiness, and withdrawal effects
`upon discontinuation. Agomelatine has been shown to attenu-
`ate sexual disorders that are induced by 5-HT 2C receptor
`agonism in rats (Loo et al, International Clinical Psychop-
`harmacology 2002, 17, 239-247; Chagraoui et al, Psychop-
`harmacology 2003, 170, 17-22; Bertaina-Anglade et al,
`Behavioural Pharmacology 2006, 17, 703-713; Kupfer,
`European Neuropsychopharmacology 2006, 16, S639-S643;
`Norman, Australian and New Zealand Journal ofPsychiatry
`2006, 40, 394-401; Montgomery, European Neuropsychop-
`harmacology 2006, 16, S633-S638; Zupancic et al, CNS
`Drugs 2006, 20(12), 981-992; Pjrek et al, Psychopharmacol-
`ogy 2007, 190, 575-579).
`
`O
`
`Fnv^
`
`MeO
`
`
`
`Agomelatine
`
`[0004] The agomelatine chemical structure contains a num-
`ber of moieties that we posit will produce clinically-inactive
`(at best) and toxic (at worst) metabolites, the formation of
`which can be prevented or diminished by the approach
`described herein. For example, agomelatine's methoxy group
`is subject to enzymatic oxidation at the C H bonds. Three
`agomelatine metabolites have been detected. The predomi-
`
`nant metabolite is a naphthol, "S 21517," that has 100-fold
`less potency for the melatonin receptor than the parent com-
`pound. Long term toxicology studies of these metabolites are
`lacking. All of these transformations, among other potential
`transformations, can and do occur through polymorphically-
`expressed enzymes thus exacerbating interpatient variability.
`Further, the terminal elimination half-life is only 2.3 hours. A
`medicine with a longer half-life will therefore attenuate inter-
`patient variatibility and improve efficacy.
`
`SUMMARY OF THE INVENTION
`
`[0005] Disclosed herein is a compound having structural
`Formula I:
`
`Formula I
`
`R15
`
`R16
`
`R5 (cid:9)
`
`R6
`
`or a pharmaceutically acceptable salt, solvate, or prodrug
`thereof, wherein:
`[0006] R1, R2, R3, R4, R5, Re, R7, R8, R9, Rio, Ri i, Rig, R13,
`R14, R15 , Rib, and R17 are independently selected from the
`group consisting hydrogen and deuterium; and
`[0007] at least one of R,, R2, R3 , R4, Rs, R6, R7, R8, R9, Rio,
`R11 , R12, R13, R14, R15, R16, and R17 is deuterium.
`[0008] Further disclosed herein is a method for treating,
`preventing, or ameliorating one or more symptoms of a mela-
`tonin (MT) receptor-mediated disorder and/or serotonin
`(5-HT) receptor-mediated disorder which comprises admin-
`istering to a subject a therapeutically effective amount of at
`least one compound as disclosed herein or a pharmaceutically
`acceptable salt, solvate, or prodrug thereof.
`[0009] Additionally disclosed herein is a method for treat-
`ing, preventing, or ameliorating one or more symptoms of a
`disorder involving, but not limited to, depressive disorders,
`seasonal affective disorders, anxiety, sleep disorders, dys-
`thymia, sexual side effects associated with the use of 5-HT 21
` agonists, any disorder which can lessened, alleviated, or ben-
`efited by modulating MT receptors, and/or any disorder
`which can lessened, alleviated, or benefited by modulating
`5-HT receptors.
`[0010] Also disclosed herein are articles of manufacture
`and kits containing compounds as disclosed herein. By way
`of example only a kit or article of manufacture can include a
`container (such as a bottle) with a desired amount of at least
`one compound (or pharmaceutical composition of a com-
`pound) as disclosed herein. Further, such a kit or article of
`manufacture can further include instructions for using said
`compound (or pharmaceutical composition of a compound)
`disclosed herein. The instructions can be attached to the con-
`
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`tamer, or can be included in a package (such as a box or a
`plastic or foil bag) holding the container.
`[0011] In another aspect is the use of a compound as dis-
`closed herein in the manufacture of a medicament for treating
`a disorder in a subject, by modulating MT receptors and/or by
`modulating 5-HT receptors. In a further or alternative
`embodiment, said disorder is depressive disorders, seasonal
`affective disorders, anxiety, sleep disorders, dysthymia,
`sexual side effects associated with the use of 5-HT 2C agonists,
`any disorder which can lessened, alleviated, or benefited by
`modulating MT receptors, and/or any disorder which can
`lessened, alleviated, or benefited by modulating 5-HT recep-
`tors.
`[0012] In another aspect are processes for preparing a com-
`pound as disclosed herein as a MT receptor modulator and/or
`a 5-HT receptor modulator, or other pharmaceutically accept-
`able derivatives such as prodrug derivatives, or individual
`isomers and mixture of isomers or enantiomers thereof.
`[0013] Also disclosed herein are processes for formulating
`pharmaceutical compositions with a compound disclosed
`herein.
`[0014] In further embodiments, said pharmaceutical com-
`position comprises a compound disclosed herein and one or
`more pharmaceutically acceptable carriers.
`[0015] In certain embodiments said pharmaceutical com-
`position comprises one or more release-controlling excipi-
`ents.
`[0016] In other embodiments said pharmaceutical compo-
`sition further comprises one or more non-release controlling
`excipients.
`[0017] In certain embodiments said pharmaceutical com-
`position is suitable for oral, parenteral, or intravenous infu-
`sion administration.
`[0018]
`In yet other embodiments said pharmaceutical com-
`position comprises a tablet, or capsule.
`[0019] In certain embodiments the compounds as disclosed
`herein are administered in a dose of 0.5 milligram to 1000
`milligram.
`[0020]
`In yet further embodiments said pharmaceutical
`compositions further comprise another therapeutic agent.
`[0021] In other embodiments said therapeutic agent is
`selected from the group consisting of antipsychotic medica-
`tions, antidepressants, 5 -HT 2c receptor modulators, endothe-
`lin converting enzyme (ECE) inhibitors, thromboxane
`enzyme antagonists, potassium channel openers, thrombin
`inhibitors, growth factor inhibitors, platelet activating factor
`(PAF) antagonists, anti-platelet agents, Factor VIa Inhibitors,
`Factor Xa Inhibitors, renin inhibitors, neutral endopeptidase
`(NEP) inhibitors, vasopepsidase inhibitors, HMG CoA
`reductase inhibitors, squalene synthetase inhibitors, fibrates,
`bile acid sequestrants, anti-atherosclerotic agents, MTP
`Inhibitors, calcium channel blockers, potassium channel acti-
`vators, alpha-PDE5 agents, beta-PDE5 agents, antiarrhyth-
`mic agents, diuretics, anti-diabetic agents, PPAR-gamma
`agonists, mineralocorticoid enzyme antagonists, aP2 inhibi-
`tors, protein tyrosine kinase inhibitors, antiinflammatories,
`antiproliferatives, chemotherapeutic agents, immunosup-
`pressants, anticancer agents, cytotoxic agents, antimetabo-
`lites, farnesyl-protein transferase inhibitors, hormonal
`agents, microtubule-disruptor agents, microtubule-stabiliz-
`ing agents, topoisomerase inhibitors, prenyl-protein trans-
`ferase inhibitors, cyclosporins, TNF-alpha inhibitors,
`cyclooxygenase-2 (COX-2) inhibitors, gold compounds, and
`platinum coordination complexes.
`
`[0022] In other embodiments said therapeutic agent is an
`antipsychotic medication.
`[0023] In further embodiments said antipsychotic medica-
`tion is selected from the group consisting of chlorpromazine,
`fluphenazine, perphenazine, prochlorperazine, thioridazine,
`trifluoperazine, haloperidol, haloperidol decanoate, droperi-
`dol, pimozide, amisulpride, aripiprazole, bifeprunox, cloza-
`pine, melperone, norclozapine, olanzapine, risperidone, pali-
`peridone, quetapine, symbyax, tetrabenazine, and
`ziprazidone.
`[0024] In other embodiments said therapeutic agent is an
`antidepressant.
`[0025] In further embodiments said antidepressant is
`selected from the group consisting of amitriptyline, bupro-
`pion, citalopram, clomipramine, dapoxetine, desipramine,
`dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine,
`imipramine, iofepramine, nortriptyline, paroxetine, protrip-
`tyline, sertraline, trazodone, trimipramine, and venlafaxine.
`[0026] In other embodiments said therapeutic agent is a
`5 -HT 2c receptor modulator.
`[0027] In yet other embodiments said 5-HT 2C receptor
`modulator is selected from the group consisting of alpha-
`methyl-5-HT, DOI, lysergic acid diethylamide (LSD), and
`mesulergine.
`[0028]
`In further embodiments, a method for the treatment,
`prevention, or amelioration of one or more symptoms of a MT
`receptor-mediated disorder, a 5-HT receptor mediated disor-
`der, or a MT receptor-mediated disorder and 5-HT receptor
`mediated disorder in a subject comprises administering a
`therapeutically effective amount of a compound as disclosed
`herein.
`[0029] In other embodiments said MT receptor-mediated
`disorder, said 5-HT receptor mediated disorder, or said MT
`receptor-mediated disorder and 5-HT receptor mediated dis-
`order is selected from the group consisting of depressive
`disorders, seasonal affective disorders, anxiety, sleep disor-
`ders, dysthymia, and sexual side effects associated with the
`use of 5-HT 2C agonists.
`[0030]
`In further embodiments, said 5-HT receptor medi-
`ated disorder, or said MT receptor-mediated disorder and
`5-HT receptor mediated disorder can be lessened, alleviated,
`or prevented by administering a 5HT receptor modulator.
`[0031] In further embodiments, said MT receptor-mediated
`disorder, or said MT receptor-mediated disorder and 5-HT
`receptor mediated disorder can be lessened, alleviated, or
`prevented by administering a MT receptor modulator.
`[0032] In other embodiments said compound has at least
`one of the following properties:
`[0033] a) decreased inter-individual variation in plasma
`levels of said compound or a metabolite thereof as com-
`pared to the non-isotopically enriched compound;
`[0034] b) increased average plasma levels of said com-
`pound per dosage unit thereof as compared to the non-
`isotopically enriched compound;
`[0035]
`c) decreased average plasma levels of at least one
`metabolite of said compound per dosage unit thereof as
`compared to the non-isotopically enriched compound;
`[0036] d) increased average plasma levels of at least one
`metabolite of said compound per dosage unit thereof as
`compared to the non-isotopically enriched compound;
`and
`[0037] e) an improved clinical effect during the treat-
`ment in said subject per dosage unit thereof as compared
`to the non-isotopically enriched compound.
`
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`US 2008/0280991 Al
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`
`[0038]
`In yet further embodiments said compound has at
`least two of the following properties:
`[0039] a) decreased inter-individual variation in plasma
`levels of said compound or a metabolite thereof as com-
`pared to the non-isotopically enriched compound;
`[0040] b) increased average plasma levels of said com-
`pound per dosage unit thereof as compared to the non-
`isotopically enriched compound;
`[0041] c) decreased average plasma levels of at least one
`metabolite of said compound per dosage unit thereof as
`compared to the non-isotopically enriched compound;
`[0042] d) increased average plasma levels of at least one
`metabolite of said compound per dosage unit thereof as
`compared to the non-isotopically enriched compound;
`and
`[0043] e) an improved clinical effect during the treat-
`ment in said subject per dosage unit thereof as compared
`to the non-isotopically enriched compound.
`[0044]
`In certain embodiments said compound has a
`decreased metabolism by at least one polymorphically-ex-
`pressed cytochrome P 450 isoform in said subject per dosage
`unit thereof as compared to the non-isotopically enriched
`compound.
`[0045]
`In other embodiments said cytochrome P 450 isoform
`is selected from the group consisting of CYP2C8, CYP2C9,
`CYP2C19, and CYP2D6.
`[0046]
`In yet further embodiments said compound is char-
`acterized by decreased inhibition of at least one cytochrome
`P450 or monoamine oxidase isoform in said subject per dosage
`unit thereof as compared to the non-isotopically enriched
`compound.
`[0047] In certain embodiments said cytochrome P 450 or
`monoamine oxidase isoform is selected from the group con-
`sisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6,
`CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18,
`CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2,
`CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1,
`CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2,
`CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1,
`CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1,
`CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17,
`CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1,
`CYP27B1, CYP39, CYP46, CYP51, MAOA, and MAOB.
`[0048]
`In other embodiments said method affects the treat-
`ment of the disorder while reducing or eliminating a delete-
`rious change in a diagnostic hepatobiliary function endpoint,
`as compared to the corresponding non-isotopically enriched
`compound.
`[0049]
`In yet further embodiments said diagnostic hepato-
`biliary function endpoint is selected from the group consist-
`ing of alanine aminotransferase ("ALT"), serum glutamic-
`pyruvic transaminase ("SGPT"), aspartate aminotransferase
`("AST," "SGOT"), ALT/AST ratios, serum aldolase, alkaline
`phosphatase ("ALP"), ammonia levels, bilirubin, gamma-
`glutamyl transpeptidase ("GGTP," "y-GTP," "GGT"), leucine
`aminopeptidase ("LAP"), liver biopsy, liver ultrasonography,
`liver nuclear scan, 5'-nucleotidase, and blood protein.
`
`INCORPORATION BY REFERENCE
`
`[0050] All publications and references cited herein, includ-
`ing those in the background section, are expressly incorpo-
`rated herein by reference in their entirety. However, with
`respect to any similar or identical terms found in both the
`incorporated publications or references and those expressly
`
`put forth or defined in this document, then those terms defi-
`nitions or meanings expressly put forth in this document shall
`control in all respects.
`
`DETAILED DESCRIPTION
`
`[0051] To facilitate understanding of the disclosure set
`forth herein, a number of terms are defined below. Generally,
`the nomenclature used herein and the laboratory procedures
`in organic chemistry, medicinal chemistry, and pharmacol-
`ogy described herein are those well known and commonly
`employed in the art. Unless defined otherwise, all technical
`and scientific terms used herein generally have the same
`meaning as commonly understood in the art to which this
`disclosure belongs. In the event that there is a plurality of
`definitions for a term used herein, those in this section prevail
`unless stated otherwise.
`[0052] As used herein, the singular forms "a," "an," and
`"the" may refer to plural articles unless specifically stated
`otherwise.
`[0053] The term "subject" refers to an animal, including,
`but not limited to, a primate (e.g., human monkey, chimpan-
`zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils,
`hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig,
`miniature pig), equine, canine, feline, and the like. The terms
`"subject" and "patient" are used interchangeably herein in
`reference, for example, to a mammalian subject, such as a
`human patient.
`[0054] The terms "treat," "treating," and "treatment" are
`meant to include alleviating or abrogating a disorder; or alle-
`viating or abrogating one or more of the symptoms associated
`with the disorder; and/or alleviating or eradicating the cause
`(s) of the disorder itself.
`[0055] The terms "prevent," "preventing," and "preven-
`tion" refer to a method of delaying or precluding the onset of
`a disorder; delaying or precluding its attendant symptoms;
`barring a subject from acquiring a disorder; and/or reducing a
`subject's risk of acquiring a disorder.
`[0056] The term "therapeutically effective amount" refers
`to the amount of a compound that, when administered, is
`sufficient to prevent development of, or alleviate to some
`extent, one or more of the symptoms of the disorder being
`treated. The term "therapeutically effective amount" also
`refers to the amount of a compound that is sufficient to elicit
`the biological or medical response of a cell, tissue, system,
`animal, or human that is being sought by a researcher, veteri-
`narian, medical doctor, or clinician.
`[0057] The term "pharmaceutically acceptable carrier,"
`"pharmaceutically acceptable excipient," "physiologically
`acceptable carrier," or "physiologically acceptable excipient"
`refers to a pharmaceutically-acceptable material, composi-
`tion, or vehicle, such as a liquid or solid filler, diluent, excipi-
`ent, solvent, or encapsulating material. Each component must
`be "pharmaceutically acceptable" in the sense of being com-
`patible with the other ingredients of a pharmaceutical formu-
`lation. It must also be suitable for use in contact with the tissue
`or organ of humans and animals without excessive toxicity,
`irritation, allergic response, immunogenecity, or other prob-
`lems or complications, commensurate with a reasonable ben-
`efit/risk ratio. See, Remington: The Science and Practice of
`Pharmacy, 21 st Edition; Lippincott Williams & Wilkins:
`Philadelphia, Pa., 2005; Handbook of Pharmaceutical
`Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceuti-
`cal Press and the American Pharmaceutical Association:
`2005; and Handbook of Pharmaceutical Additives, 3rd Edi-
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`tion; Ash and Ash Eds., Gower Publishing Company: 2007;
`Pharmaceutical Preformulation and Formulation, Gibson
`Ed., CRC Press LLC: Boca Raton, Fla., 2004).
`[0058] The term "deuterium enrichment" refers to the per-
`centage of incorporation of deuterium at a given position in a
`molecule in the place of hydrogen. For example, deuterium
`enrichment of 1% at a given position means that 1% of mol-
`ecules in a given sample contain deuterium at the specified
`position. Because the naturally occurring distribution of deu-
`terium is about 0.0156%, deuterium enrichment at any posi-
`tion in a compound synthesized using non-enriched starting
`materials is about 0.0156%. The deuterium enrichment can
`be determined using conventional analytical methods, such as
`mass spectrometry and nuclear magnetic resonance spectros-
`copy.
`[0059] The term "is/are deuterium," when used to describe
`a given position in a molecule such as R 1 , R2 , R3 , R4, R5 , R6 ,
`R7, R8, R9, R10, R11 , R12, R13 , R14, R15 , R16 and R17 or the
`symbol "D," when used to represent a given position in a
`drawing of a molecular structure, means that the specified
`position is enriched with deuterium above the naturally
`occurring distribution of deuterium. In an embodiment deu-
`terium enrichment is of no less than about 1%, in another no
`less than about 5%, in another no less than about 10%, in
`another no less than about 20%, in another no less than about
`50%, in another no less than about 70%, in another no less
`than about 80%, in another no less than about 90%, or in
`another no less than about 98% of deuterium at the specified
`position.
`[0060] The term "isotopic enrichment" refers to the per-
`centage of incorporation of a less prevalent isotope of an
`element at a given position in a molecule in the place of the
`more prevalent isotope of the element.
`[0061] The term "non-isotopically enriched" refers to a
`molecule in which the percentages of the various isotopes are
`substantially the same as the naturally occurring percentages.
`[0062] The terms "substantially pure" and "substantially
`homogeneous" mean sufficiently homogeneous to appear
`free of readily detectable impurities as determined by stan-
`dard analytical methods, including, but not limited to, thin
`layer chromatography (TLC), gel electrophoresis, high per-
`formance liquid chromatography (HPLC), nuclear magnetic
`resonance (NMR), and mass spectrometry (MS); or suffi-
`ciently pure such that further purification would not detect-
`ably alter the physical and chemical properties, or biological
`and pharmacological properties, such as enzymatic and bio-
`logical activities, of the substance. In certain embodiments,
`"substantially pure" or "substantially homogeneous" refers to
`a collection of molecules, wherein at least about 50%, at least
`about 70%, at least about 80%, at least about 90%, at least
`about 95%, at least about 98%, at least about 99%, or at least
`about 99.5% of the molecules are a single compound, includ-
`ing a racemic mixture or single stereoisomer thereof, as deter-
`mined by standard analytical methods.
`[0063] The term "about" or "approximately" means an
`acceptable error for a particular value, which depends in part
`on how the value is measured or determined. In certain
`embodiments, "about" can mean 1 or more standard devia-
`tions.
`[0064] The terms "active ingredient" and "active sub-
`stance" refer to a compound, which is administered, alone or
`in combination with one or more pharmaceutically accept-
`able excipients and/or carriers, to a subject for treating, pre-
`venting, or ameliorating one or more symptoms of a disorder.
`
`[0065] The terms "drug," "therapeutic agent," and "chemo-
`therapeutic agent" refer to a compound, or a pharmaceutical
`composition thereof, which is administered to a subject for
`treating, preventing, or ameliorating one or more symptoms
`of a disorder.
`[0066] The term "disorder" as used herein is intended to be
`generally synonymous, and is used interchangeably with, the
`terms "disease," "sydrome" and "condition" (as in medical
`condition), in that all reflect an abnormal condition of the
`body or of one of its parts that impairs normal functioning and
`is typically manifested by distinguishing signs and symp-
`toms.
`[0067] The term "release controlling excipient" refers to an
`excipient whose primary function is to modify the duration or
`place of release of the active substance from a dosage form as
`compared with a conventional immediate release dosage
`form.
`[0068] The term "nonrelease controlling excipient" refers
`to an excipient whose primary function do not include modi-
`fying the duration or place of release of the active substance
`from a dosage form as compared with a conventional imme-
`diate release dosage form.
`[0069] The term "Melatonin receptor" or "MT receptor"
`refers to receptors which bind the hormone melatonin. For
`example, "Melatonin receptor" or "MT receptor" would
`include the G-protein coupled melatonin M, receptor (also
`known as MTNRIA) and the G-protein coupled melatonin
`M2 receptor (also known as MTNR1 B).
`[0070] The term "5-HT receptor" refers to the receptors for
`the neurotransmitter and peripheral signal mediator seroto-
`nin, also known as 5-hydroxytryptamine or 5-HT. 5-HT
`receptors are located on the cell membrane of nerve cells and
`other cell types including smooth muscle in animals, and
`mediate the effects of serotonin (the endogenous ligand) as
`well as a broad range of pharmaceutical and hallucinogenic
`drugs. 5-HT receptors affect the release and activity of other
`neurotransmitters such as glutamate, dopamine and GABA.
`The term "5-HT receptor" refers to all the various subtypes of
`the 5-HT receptor. For example, "5-HT receptor" would
`include the 5-HT 2C receptor. 5-HT 2c receptors may control
`intracellular levels of inositol triphosphate (IP 3) and/or dia-
`cylglycerol (DAG). The 5-HT 2c receptor was formerly called
`the "5-HT, c receptor" in some previous publications.
`[0071] The term "MT receptor modulator" or "modulation
`of MT receptors" refers to the ability of a compound disclosed
`herein to alter the function of an MT receptor. A modulator
`may activate the activity of an MT receptor, may activate or
`inhibit the activity of an MT receptor depending on the con-
`centration of the compound exposed to the MT receptor, or
`may inhibit the activity of an MT receptor. Such activation or
`inhibition may be contingent on the occurrence of a specific
`event, such as activation of a signal transduction pathway,
`and/or may be manifest only in particular cell types. The term
`"MT receptor modulator" or "modulation of MT receptors"
`also refers to altering the function of an MT receptor by
`increasing or decreasing the probability that a complex forms
`between an MT receptor and a natural binding partner. A MT
`receptor modulator may increase the probability that such a
`complex forms between the MT receptor and the natural
`binding partner, may increase or decrease the probability that
`a complex forms between the MT receptor and the natural
`binding partner depending on the concentration of the com-
`pound exposed to the MT receptor, and or may decrease the
`probability that a complex forms between the MT receptor
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`Apotex Ex. 1009
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`US 2008/0280991 Al
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`Nov. 13, 2008
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`and the natural binding partner. In some embodiments, modu-
`lation of the MT receptor may be assessed using Receptor
`Selection and Amplification Technology (R-SAT) as
`described in U.S. Pat. No. 5,707,798, the disclosure of which
`is incorporated herein by reference in its entirety.
`[0072] The term "5HT receptor modulator" or "modulation
`of 5HT receptors" refers to the ability of a compound dis-
`closed herein to alter the function of a 5HT receptor. A modu-
`lator may activate the activity of a 5HT receptor, may activate
`or inhibit the activity of a 5HT receptor depending on the
`concentration of the compound exposed to the 5HT receptor,
`or may inhibit the activity of a 5HT receptor. Such activation
`or inhibition may be contingent on the occurrence of a spe-
`cific event, such as activation of a signal transduction path-
`way, and/or may be manifest only in particular cell types. The
`term "5HT receptor modulator" or "modulation of 5HT
`receptors" also refers to altering the function of a 5HT recep-
`tor by increasing or decreasing the probability that a complex
`forms between a 5HT receptor and a natural binding partner.
`A 5HT receptor modulator may increase the probability that
`such a complex forms between the 5HT receptor and the
`natural binding partner, may increase or decrease the prob-
`ability that a complex forms between the 5HT receptor and
`the natural binding partner depending on the concentration of
`the compound exposed to the 5HT receptor, and or may
`decrease the probability that a complex forms between the
`5HT receptor and the natural binding partner. In some
`embodiments, modulation of the 5HT receptor may be
`assessed using Receptor Selection and Amplification Tech-
`nology (R-SAT) as described in U.S. Pat. No. 5,707,798, the
`disclosure of which is incorporated herein by reference in its
`entirety.
`[0073] The term "protecting group" or "removable protect-
`ing group" refers to a group which, when bound to a func-
`tionality, such as the oxygen atom of a hydroxyl or carboxyl
`group, or the nitrogen atom of an amino group, prevents
`reactions from occurring at that functional group, and which
`can be removed by a conventional chemical or enzymatic step
`to reestablish the functional group (Greene and Wuts, Protec-
`tive Groups in Organic Synthesis, 3 d d Ed., John Wiley &
`Sons, New York, N.Y., 1999).
`[0074] The term "halogen", "halide" or "halo" includes
`fluorine, chlorine, bromine, and iodine.
`[0075] The term "chlorinating reagent" refers to a reactive
`chemical reagent used in chlorination reactions, whereby
`chlorine is transferred to a substrate. Examples of chlorinat-
`ing agents include, but are not limited to, thionyl chloride,
`chlorine gas, carbon tetrachloride, cyanuric chloride,
`hexachloro-2-propanone, N-chlorosuccinimide, phosphorus
`oxychloride, phosphorus pentachloride, phosphorus trichlo-
`ride, phosphorus (V) oxychloride, and sulfuryl chloride.
`[0076] The term "catalyst" refers to a substance, which
`increases the rate of a chemical reaction, which itself is not
`consumed in an overall chemical or biological reaction. More
`generally, one may at times call anything that accelerates a
`process, a "catalyst" (From the Greek xatiaXUELV, meaning
`to annul or to untie or to pick up). A "catalyst" does not allow
`for a reaction to take place, but it provides an alternative route
`to products, the catalytic route being subject to lower activa-
`tion energy than in the uncatalyzed reaction. A lowered acti-
`vation energy increases the reaction rate. Catalysts generally
`change in the course of a reaction but are regenerated.
`[0077] The term "reducing reagent" refers to any reagent
`that will decrease the oxidation state of an atom in the starting
`
`material by either adding a hydrogen to this atom, or adding
`an electron to this atom, or by removing an oxygen from this
`atom and as such would be obvious to one of ordinary skill
`and knowledge in the art. The definition of "reducing reagent"
`includes but is not limited to: borane-dimethyl sulfide com-
`plex, 9-borabicyclo[3.3.1.]nonarse (9-BBN), catechol
`borane, lithium borohydride, lithium borodeuteride, sodium
`borohydride, sodium borodeuteride, sodium borohydride-
`methanol complex, potassium borohydride, sodium hydroxy-
`borohydride, lithium triethylborohydride, lithium n-butyl-
`borohydride, sodium cyanoborohydride, sodium
`cyanoborodeuteride, calcium (II) borohydride, lithium alu-
`minum hydride, lithium aluminum deuteride, diisobutylAlu-
`minum hydride, n-butyl-diisobutylaluminum hydride,
`Sodium bis-methoxyethoxyAluminum hydride, triethoxysi-
`lane, diethoxymethylsilane, lithium hydride, lithium,
`sodium, hydrogen Ni/B, and the like. Certain acidic and
`Lewis acidic reagents enhance the activity of reducing
`reagents. Examples of such acidic reagents include: acetic
`acid, methanesulfonic acid, hydrochloric acid, and the like.
`Examples of such Lewis acidic reagents include: trimethox-
`yborane, triethoxyborane, aluminum trichloride, lithium
`chloride, vanadium trichloride, dicyclopentadienyl titanium
`dichloride, cesium fluoride, potassium fluoride, zinc (II)
`chloride, zinc (II) bromide, zinc (II) iodide, and the like.
`[0078] The terms "alkyl" and "substituted alkyl" are inter-
`changeable and include substituted, optionally substitu